A self-sustaining molecular pacemaker within the hypothalamus allows organisms to organize physiology and behavior around the light-dark cycle. In mammals, the CLOCK protein is an essential component of this pacemaker. A mouse strain with a dominant negative mutation in the Clock gene displays lengthened and/or arrhythmic locomotor activity in the absence of entraining cues, and we have recently determined that this strain also has pleiotropic reproductive defects. Female Clock homozygous mice display altered luteinizing hormone (LH) release irregular estrous cycles, and mid-gestational pregnancy failure. In the present proposal, we hypothesize that both the estrous cyclicity and gestational defects are due to altered output from the central pacemaker to the neurons responsible for controlling LH and prolactin release, respectively. We propose to identify the nature of the circadian output signal to these neurons, and to test this hypothesis by manipulating the candidate output signal in wild type and mutant animals. [unreadable] [unreadable]